Case study
I was on glatiramer acetate (Copaxone) for around 3 years until 2016 - at age 51. After having a regular menstrual cycle for over 30 years, from the month I first started Copaxone until the month after I stopped Copaxone, my menstrual cycle completely stopped. Out of curiosity, during that time, I ceased Copaxone for a few days, I did this probably 3 times over the 3 years. Each time I did this it triggered a period.
With menopause on the horizon, I became concerned about the long term effects of Copaxone stopping my periods. My neurologist denied the involvement of Copaxone citing menopause to be the reason for my periods stopping, but it was too much of a coincidence for me and I was worried so decided to come off it and did not start another DMT. The month after stopping the injections, at the age of 51, my periods restarted with regularity which lasted for a year or so before slowing down to 6 or 9 months apart.
At age 54 I started bleeding lightly continuously with the GP stating it was probably menopause. I returned to the GP recently at age 56 with heavy bleeding and was referred for an ultrasound which revealed my endometrium is 30mm thick.
My reason for contacting you is to ask if you have any information regarding Copaxone and its effects on menstrual cycles/hormones/menopause. I have found comments online written by other women experiencing menstrual issues with Copaxone but have found nothing official.
I asked my gynaecologist what he thought about all of this, he replied it's hard to say, though I imagine he is probably not very familiar with Copaxone and I have only seen him once so far.
I am booked for hysteroscopy with general anaesthetic due to spasms from the waist down.
Prof G’s opinion
I have done a search using PubMed and have no reports of glatiramer acetate (GA) or Copaxone affecting menstruation or the timing of menopause. Similarly, when you interrogate the summary of product characteristics there is no mention that GA affects fertility, response to contraception, menstruation or menopause. However, when you search on Google there are a lot of queries from people with MS with menstrual problems on GA. I, therefore, suspect the latter may be coincidental as GA is a commonly prescribed DMT and menstrual problems are very common.
This is the text from the current Copaxone SmPC:
4.6 Fertility, pregnancy and lactation
Pregnancy
Studies in animals have not shown reproductive toxicity (see section 5.3). Current data on the use of Copaxone 20 mg/ml in pregnant women indicate no malformative or feto/neonatal toxicity. Data on the use of Copaxone 40 mg/ml are consistent with these findings. To date, no relevant epidemiological data are available. As a precautionary measure, it is preferable to avoid the use of Copaxone during pregnancy unless the benefit to the mother outweighs the risk to the foetus.
Breastfeeding
The physico-chemical properties and low oral absorption suggest that exposure of newborns/infants to glatiramer acetate via human breast milk is negligible. A non-interventional retrospective study in 60 breastfed infants of mothers exposed to glatiramer acetate compared to 60 breastfed infants of mothers not exposed to any disease modifying therapy and limited post-marketing human data showed no negative effects of glatiramer acetate. Copaxone can be used during breastfeeding.
Glatiramer acetate
The problem with GA is that its real mode of action is unknown. What we do know is that it takes several months for GA to have its full therapeutic effect in MS and similarly many months for its therapeutic effects to wear off. The latter is probably due to it working via immune cell networks. Based on this mode of action it is hard to link these GA-induced immune changes to the menstrual cycle. In your case, the challenge-rechallenge with GA suggests it may be having an effect on you, but it is very difficult to explain this scientifically based on the mode of action of GA. I would tend to agree with your neurologist that your irregular periods were likely to be due to being perimenopausal rather than being due to GA.
As you are probably aware the menstrual cycle is controlled by a well-defined hormonal cycle and there is no evidence that GA affects the endocrine system or has effects on hormones or hormonal cycles.
Menopause
It is clear from your age and history of irregular periods that you were perimenopausal. Menopause is essentially the end-stage of a process in which the ovaries run out of eggs and fail. The loss of ovarian function is gradual and probably includes an asymptomatic phase, followed by a prodromal phase (symptoms in the presence of apparently normal function, i.e. regular periods), followed by honeymooning or perimenopause in the case of endocrine failure (irregular periods) and finally by overt failure, i.e. the menopause (loss of periods or ovulation).
In a similar way to radiologically-isolated syndrome (RIS) or asymptomatic MS, the medical profession does not identify asymptomatic or prodromal ovarian dysfunction as being perimenopausal, which is why NICE does not recommend HRT in women who are having regular periods. I am aware that several commentators to my recent MS-Selfie Newsletter think differently and make the point that even in women who are still having regular periods HRT may help with many symptoms that are compatible with low oestrogen levels. I don’t disagree, but as a neurologist, I don’t have the ability to prescribe HRT or change national guidelines.
NICE Guidance on HRT on the NHS in England
1.2 Diagnosis of perimenopause and menopause
1.2.1. Diagnose the following without laboratory tests in otherwise healthy women aged over 45 years with menopausal symptoms:
perimenopause based on vasomotor symptoms and irregular periods
menopause in women who have not had a period for at least 12 months and are not using hormonal contraception
menopause based on symptoms in women without a uterus.
1.2.2. Take into account that it can be difficult to diagnose menopause in women who are taking hormonal treatments, for example for the treatment of heavy periods.
1.2.3. Do not use the following laboratory and imaging tests to diagnose perimenopause or menopause in women aged over 45 years:
anti-Müllerian hormone
inhibin A
inhibin B
oestradiol
antral follicle count
ovarian volume.
1.2.4. Do not use a serum follicle-stimulating hormone (FSH) test to diagnose menopause in women using combined oestrogen and progestogen contraception or high-dose progestogen.
1.2.5. Consider using an FSH test to diagnose menopause only:
in women aged 40 to 45 years with menopausal symptoms, including a change in their menstrual cycle
in women aged under 40 years in whom menopause is suspected (see also recommendations on diagnosing and managing premature ovarian insufficiency).
Menopause cont.
Most general practitioners or family doctors are reluctant to investigate women with low oestrogen levels who are having regular periods. Clearly, women who are on hormonal therapies, e.g. the contraceptive pill, have progesterone releasing IUD (Mirena) in situ or have had a hysterectomy are different and would need studies done to assess if they are menopausal and need HRT.
You are probably aware that there is some evidence that HRT may be disease-modifying in MS, which is why I recommend to my female patients with MS who are perimenopausal or menopausal to consider starting HRT provided there are no contraindications.
I have discussed HRT and its potential as a DMT in a previous Newsletter; ‘Is it MS or is it menopause?’ (5-Aug-2021). HRT is not only good for brain health but has positive effects on your metabolism and bone health. Saying this it looks as if you do have a contraindication for HRT; postmenopausal bleeding with a thickened endometrium. This is very worrying and I agree with your GP that it needs investigation urgently. The biopsy is urgent to exclude a premalignant or malignant condition.
Endometrial conditions tend to be hormone-responsive, which is why oestrogen containing HRT is a contraindication. Although not relevant to you I have many patients with MS who I recommend suppression of menstruation to help them with managing their MS. This could be a personal choice, to help with hygiene in disabled patients and to help with worsening symptoms associated with menstruation. Please note there are several options available today to suppress menstruation and this is usually managed by the general practitioner and includes (1) continuous combined or progesterone-only contraceptive pills, (2) the progesterone releasing IUD (Mirena), (3) depot medroxyprogesterone acetate (Depo-Provera) and (4) GnRH analogues. The latter is usually used to try and protect the ovaries from chemotherapy-induced toxicity, which may be relevant to women with MS considering AHSCT.
Please note I am not a gynaecologist or endocrinologist so my advice may not be up-to-date and I would therefore defer to these specialities for detailed personal advice.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
Case study: Copaxone, menstruation and the menopause